The Aquaporin Family
The aquaporins are a family of small (24-30 kDa) pore-forming integral membrane proteins characterized by six transmembrane helices that selectively allow water or other small uncharged molecules to pass along an osmotic gradient. These proteins form tetramers, with each monomer defining a single pore. The aquaporin protein family was first named after the major intrinsic protein (MIP) of the mammalian lens, which is now designated AQP0. When MIP homologs were eventually shown to function as water channels, the name aquaporin was adopted for the family. The aquaporin family has representatives in all kingdoms, including archaea, eubacteria, fungi, plants and animals. The MIP homologs with exclusive water permeability are referred to as aquaporins, whereas water- and glycerol-permeable homologs are referred to as aquaglyceroporins. In vertebrates, eleven different aquaporins have so far been identified, corresponding to the human proteins AQP0-AQP10. Of these, seven aquaporins (AQP0, AQP1, AQP2, AQP4, AQP5, AQP6, and AQP8) have been characterized as the classical aquaporins that promote water transport in mammals. The other four aquaporins (AQP3, AQP7, AQP9 and AQP10) promote glycerol transport in mammals and have, thus, been assigned to the GLP subfamily. Additional aquaporins have been identified in E. coli, yeast and plants (Kruse et al. (2006) Genome Biology 7(2)(206):1-6).
The first member of the aquaporin family that was extensively described was the channel-like integral membrane protein of the human erythrocyte membrane. This protein was originally known as the 28 kDa protein CHIP28. Based on functional analyses, this protein was later renamed aquaporin-1 (AQP1). Experiments with the primary protein sequence of aquaporin-1 (AQP1) predicted six transmembrane helices (I-VI) connected by five loops (loops A-E). Loops A, C and E are extracellular and loops B and D are intracellular. In addition, the protein comprises two internal tandem repeats, covering roughly the amino- and carboxy-terminal halves of the protein. Each repeat consists of three transmembrane helices and a highly conserved loop following the second transmembrane helix (loops B and E, respectively). This loop includes the conserved signature motif, asparagine-proline-alanine (NPA). Loops B and E form short a helices that fold back into the membrane, with loop B entering the membrane from the cytoplasmic side and loop E from the extracellular side. A seventh transmembrane domain in which the two NPA boxes are orientated 180 degrees to each other is thus formed, creating an aqueous pathway through the proteinaceous pore. Since all aquaporins are structurally related and have highly similar consensus regions, particularly in the pore-forming domains, a similar transport mechanism is likely. The hydrophobic domain created by the loops B and E has been suggested to be involved in substrate specificity and/or size restriction. The pathway through the aquaporin monomer is lined with conserved hydrophobic residues that permit rapid transport of water in the form of a single-file hydrogen-bonded chain of water molecules. The pore contains two constriction sites, i.e., an aromatic region comprising a conserved arginine residue (Arg195) forms the narrowest part of the pore, while the highly conserved NPA motifs form a second filter, where single water molecules interact with the two asparagine side chains. Since there is a direct interaction between water molecules and the NPA motifs, the dipolar water molecule rotates 180 degrees during passage through the pore. Both filter regions build up electrostatic barriers, which prevent the permeation of protons. In human AQP1, a hydrophobic phenylalanine side chain (Phe24) intrudes into the pore and enhances the interaction of single permeating water molecules with the NPA loops. In fact, Phe24 acts as a size-exclusion filter, preventing the passage of larger molecules such as glycerol through AQP1. The water permeabilities for human aquaporins are estimated to be between 0.25×10−14 cm3/sec for AQP0 and 24×10−14 cm3/sec for AQP4. However, aquaporins are believed to have different requirements for osmoregulation and transmembrane water movement in different tissues, organs and developmental stages. In mammals, aquaporins are localized in epithelia that need a high rate of water flux, such as the collecting duct of the kidney, the capillaries of the lung, and the secretory cells of the salivary glands. In addition, mammalian aquaporins differ in their transcriptional regulation, post-transcriptional regulation and subcellular distribution (Kruse et al. (supra)).
Edema
Edema is the swelling of tissues that occurs when excessive fluid accumulates within those tissues. Edema is a symptom of systemic diseases, i.e., diseases that affect the various organ systems of the body. It may be caused by local conditions involving just the affected extremities. In peripheral edema, the swelling is the result of the accumulation of too much fluid under the skin in the spaces within the tissues, also known as the interstitial spaces or interstitium made up of connective tissue. Most bodily fluids that are found outside of the cells are normally stored in the blood vessels and the interstitial spaces. In various diseases and under certain conditions, excess fluid can accumulate in either one or both of these compartments. The most common local conditions that cause edema are varicose veins and thrombophlebitis, i.e., inflammation of the veins of the deep veins of the legs. These conditions can lead to inadequate pumping of the blood by the veins which in turn leads to venous insufficiency. The resulting increased back-pressure in the veins forces fluid to stay in the extremities, particularly in the ankles and feet. The excess fluid then leaks into the interstitial spaces, causing edema. Although, the swelling may be limited to specific areas like the lower limbs, it may also spread over large areas of the body. Systemic edema is most commonly associated with heart, liver and kidney diseases. It occurs primarily because the body retains too much salt, i.e., sodium chloride. The excess salt causes the body to retain water. This water then leaks into the interstitial spaces, where it appears as edema.
In general, edema is classified by the location of the swelling tissue. There are numerous examples such as peripheral edema which is mainly swelling of the lower limbs; pulmonary edema which is accumulation of fluid in the lungs; periorbital edema which is swelling around the eyes; ocular edema which is fluid retention in the cornea; cerebral edema which is swelling of brain tissue; ascites (excess fluid in the abdomen); massive edema (i.e., anasarca) which is swelling that covers a large part of the body; and the like. Other body locations that may become swollen include the gums, lymph glands, face, abdomen, breasts, scrotum, liver, and the joints. The signs and symptoms of edema vary depending on the location of the tissue and the extent of the swelling. For many types of edema, fluid builds up under the skin, causing swelling and making the overlying area stretched and shiny. Edema can be pitting or non-pitting. In pitting edema, pressing a finger against a swollen area and then removing it leaves an indentation that slowly disappears. When edema becomes more severe, the tissue swells so much that it cannot be displaced, and no indentation is left in the skin after applying pressure such as in non-pitting edema. Edema that occurs over pressure points over bony areas of the body can develop into serious sores or ulcers, especially in bedridden patients.
Edema is also known to be itself a symptom associated with several different underlying diseases such as kidney, liver, and heart disease. Hence, edema can be a long-term and progressive manifestation of a disorder with serious consequences. For example, pulmonary edema can be a complication of heart failure. As the heart pumps less efficiently, fluid leaks out of the veins in the lungs and fills the air sacs or alveoli, making it difficult to breathe. Pulmonary edema can become life-threatening, and if left untreated, can rapidly lead to death. Symptoms of pulmonary edema include shortness of breath, grunting while breathing, a crackling or rattling noise in the lungs noticeable with a stethoscope (rales), wheezing, anxiety, restlessness, coughing, excessive sweating, abnormally pale skin (pallor), abnormal heartbeat or rhythm, and chest pain. However, even patients with less severe heart failure that may not lead to pulmonary edema can still experience serious swelling in their lower limbs. Edema can also be caused by chronic lung disease. Severe chronic lung disease, such as chronic obstructive pulmonary disease (COPD), emphysema, or chronic bronchitis can restrict blood flow in the blood vessels in the lungs. The restricted blood flow creates pressure in the blood vessels that can back up throughout the rest of the circulatory system. This pressure, in turn, causes fluid to leak into surrounding tissues, causing swelling, i.e., edema, such as in the legs and feet.
Additional causes of edema are varicose veins (as a result of blood pooling in the lower legs); long sitting or standing as in orthostatic edema (e.g., as a result of hot weather, long plane and automobile rides); certain medications (e.g., oral contraceptives containing estrogen or progesterone, blood pressure medications, certain antidepressants, oral corticosteroids, testosterone); pregnancy (as a result of increased blood pressure in the lower limbs which can be due to preeclampsia); allergic reactions; sunburns; malnutrition, injury or trauma; blockages in the lymphatic system (e.g., caused by infection, inflammation, or cancer), exposure to high altitude as in high altitude edema; hormonal changes associated with menstruation in some women; nephrotic syndrome (in which damaged kidneys lose excess protein in the urine leading to severe swelling in the ankles); and severe liver disease (leading to cirrhosis and excess ankle swelling).
Since edema is often a symptom of another underlying condition, the risk factors for edema are the same as those for the underlying conditions. As such, the same risk factors as in kidney, liver, heart, and lung disease apply to edema. For example, smoking is a major risk factor for chronic lung disease, high blood pressure is a major risk factor for heart disease, and obesity is a major risk factor for both heart disease and diabetes. All of these risk factors also increase a subject's risk of developing edema. In addition, edema occurs more commonly in individuals with older age because many of the underlying causes of edema occur more frequently in older populations.